US4843073A - 1-t-butyl ergolines useful in the treatment of cerebral insufficiency and senile dementia - Google Patents

1-t-butyl ergolines useful in the treatment of cerebral insufficiency and senile dementia Download PDF

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US4843073A
US4843073A US07/065,597 US6559787A US4843073A US 4843073 A US4843073 A US 4843073A US 6559787 A US6559787 A US 6559787A US 4843073 A US4843073 A US 4843073A
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ergoline
butyl
methyl
pharmaceutically acceptable
methoxy
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Aldemio Temperilli
Enzo Brambilla
Mauro Gobbini
Maria A. Cervini
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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  • the invention relates to ergoline derivatives, to processes for their preparation and to pharmaceutical compositions containing ergoline derivatives.
  • the 1-alkylation of ergolines may be performed by reacting non-alkylated ergolines with alkyl halides in liquid ammonia in the presence of a strong base such as potassium amide (see Troxler F., Hofmann A., Helv. Chim. Acta, 40 2160 (1957)).
  • a strong base such as potassium amide
  • the efficiency of this alkylation reaction is good for primary alkyl halides, but much reduced for secondary alkyl halides.
  • Tertiary alkyl halides do not react at all but instead yield the related olefins by elimination.
  • One object of this invention is to provide processes for the preparation of 1-tertiaryalkyl ergoline derivatives, for example, 1-t-butyl ergoline derivatives.
  • Another object of this invention is to provide 1tertiaryalkyl ergoline derivatives, for example, 1-t-butyl ergoline derivatives, which are useful as therapeutic agents.
  • Another object of this invention is to provide pharmaceutical compositions containing such ergoline derivatives.
  • R 1 and R 2 taken together represent a ring bond
  • R 1 is a hydrogen atom or a methoxy group and R 2 is a hydrogen atom;
  • R 3 is a hydrogen atom, a nicotinoyl group, a substituted nicotinoyl group, or a 1-oxo-2-cyclopenten-3-yl group;
  • R 4 is a C 1 -C 4 alkyl; or
  • Lysergol (II) can be t-alkylated, e.g., t-butylated, at position 1 of the ergoline skeleton by reacting ergoline with tertiary alcohol, e.g., t-butanol, in trifluoroacetic anhydride for a period of from 70 to 90 hours at a temperature between 15°-30° C. and, preferably between 20°-25° C. This reaction may be carried out in the presence or absence of other organic solvents, such as benzene, DMF or dioxane.
  • R 1 and R 2 taken together represent a ring bond
  • R 3 represents a hydrogen atom
  • R 4 is independently a C 1 -C 4 alkyl, preferably methyl.
  • R 3 represents a substituted nicotinoyl group
  • the substituent is preferably an alkyl group having from to 4 carbon atoms, a nitro, cyano, hydroxy, amino or aminomethyl group, or a halogen atom such as a bromine atom.
  • R 4 is independently a C 1-4 alkyl group, preferably methyl, such that (R 4 ) 3 C is a t-alkyl group.
  • the compounds of the invention may be administered in the form of a pharmaceutically acceptable acid addition salt.
  • Such salt forms have the same order of activity as the free base forms.
  • the tertiary alkyl ergoline derivatives of the invention may be produced by reacting lysergol with an excess quantity of a tertiary alkyl alcohol, e.g., t-butanol, in the presence of a catalytic amount of trifluroacetic anhydride, in the presence or absence of an inert organic solvent, at a temperature between 15° and 30° C. for 70 to 90 hours, preferably at 20°-25° C. for 70-90 hours.
  • a tertiary alkyl alcohol e.g., t-butanol
  • the 1-tertiary alkylated lysergol is then either hydrogenated in the presence of a noble metal catalyst, or alkoxylated upon UV irradiation in the presence of an alcohol and sulfuric acid, to form a 1-tertiaryalkylergoline derivative.
  • the compounds of the general formula I wherein R 3 represents a hydrogen atom may be converted into other compounds of the general formula I using normal chemical reactions.
  • esterification of the C-17 hydroxy group is effected by treatment with the anhydride or chloride of an organic acid in the optional presence of a tertiary amine such as pyridine, triethylamine and the like, according to the method described in U.S. Pat. No. 3,228,943 (incorporated by reference herein).
  • the etherification is effected by treatment of the corresponding tosyl esters with 1,3-dicarbonyl compounds in sodium salt form in hexamethylphosphotriamide as solvent as described in U.S. Pat. No. 4,382,940 (incorporated by reference herein).
  • this etherification is carried out by reaction with 1,3-cyclopentendione for 2-4 hours at a temperature between 70° C.-100° C.
  • the oral orientative acute toxicity (LD 50 ) of the compounds of the formula I was higher than 800 mg/kg.
  • the compounds are therefore useful in the treatment of cerebral insufficiency and senile dementia, particularly the early stages thereof.
  • the dosage will, of course, vary depending on the compound employed, mode of administration and treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from 0.001 mg to about 50 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form.
  • the total daily dosage is in the range of from 1 to about 100, preferably 10 to 90 mg, and dosage forms suitable for oral administration comprise from about 0.2 mg to about 50 mg of the compounds admixed with a solid or liquid pharmaceutically acceptable carrier or diluent, such as starch, lactose, dextrin, magnesium stearate or water.
  • a solid or liquid pharmaceutically acceptable carrier or diluent such as starch, lactose, dextrin, magnesium stearate or water.
  • the present invention accordingly provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one ergoline derivative I as herein defined or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
  • Such compositions may be formulated in a conventional manner so as to be, for example, a solution or a tablet.
  • the compounds of the present invention may be used in an analogous manner to standard compounds used for the indications mentioned above.
  • the solution was diluted with iced water, made basic with ammonium hydroxide, evaporated to 100 ml and extracted with ethyl acetate.

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Abstract

t-Alkyl ergoline derivatives of formula I are produced ##STR1## wherein (R1 =H, OCH3 and R2 =H) or (R1 +R2 =a ring bond and R3 =H, optionally substituted nicotinoyl or 1-oxo-2-cyclopenten-3-yl); and their pharmaceutically acceptable salts.
A process for the preparation of these derivatives from lysergol and a t-alkyl alcohol is also described, as are pharmaceutical compositions containing them.

Description

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to ergoline derivatives, to processes for their preparation and to pharmaceutical compositions containing ergoline derivatives.
2. Discussion of the Background
The 1-alkylation of ergolines may be performed by reacting non-alkylated ergolines with alkyl halides in liquid ammonia in the presence of a strong base such as potassium amide (see Troxler F., Hofmann A., Helv. Chim. Acta, 40 2160 (1957)). The efficiency of this alkylation reaction is good for primary alkyl halides, but much reduced for secondary alkyl halides. Tertiary alkyl halides do not react at all but instead yield the related olefins by elimination.
The prior art has not disclosed a suitable methodology for the addition of a tertiary alkyl group to the 1 position of the ergoline molecule.
SUMMARY OF THE INVENTION
One object of this invention is to provide processes for the preparation of 1-tertiaryalkyl ergoline derivatives, for example, 1-t-butyl ergoline derivatives.
Another object of this invention is to provide 1tertiaryalkyl ergoline derivatives, for example, 1-t-butyl ergoline derivatives, which are useful as therapeutic agents.
Another object of this invention is to provide pharmaceutical compositions containing such ergoline derivatives.
These and other objects as will hereinafter become more clear from the following disclosure have been attained by preparing 1-(tertiaryalkyl)-ergoline derivatives, e.g. 1-t-butyl ergoline, by using a tertiary alcohol, e.g., t-butanol in trifluoroacetic anhydride, under conditions that one would have expected to lead to electrophilic bonding to position 2 of the ergoline ring or in the aromatic ring. This results in the production of an ergoline derivative of the formula ##STR2## wherein:
R1 and R2 taken together represent a ring bond; or
R1 is a hydrogen atom or a methoxy group and R2 is a hydrogen atom; or
R3 is a hydrogen atom, a nicotinoyl group, a substituted nicotinoyl group, or a 1-oxo-2-cyclopenten-3-yl group; R4 is a C1 -C4 alkyl; or
a pharmaceutically acceptable salt thereof
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Lysergol (II) can be t-alkylated, e.g., t-butylated, at position 1 of the ergoline skeleton by reacting ergoline with tertiary alcohol, e.g., t-butanol, in trifluoroacetic anhydride for a period of from 70 to 90 hours at a temperature between 15°-30° C. and, preferably between 20°-25° C. This reaction may be carried out in the presence or absence of other organic solvents, such as benzene, DMF or dioxane. ##STR3## wherein R1 and R2 taken together represent a ring bond, and R3 represents a hydrogen atom, and R4 is independently a C1 -C4 alkyl, preferably methyl.
The tertiary alkyl lysergol, e.g., t-butyl-lysergol, so obtained may be transformed into a 10-methoxy derivative, according to the process of U.S. Pat. No. 3,647,655 or reduced to the dihydro derivative by reduction with hydrogen in the presence of a noble metal.
The ergoline derivatives of the present invention have the formula I ##STR4## wherein either R1 represents a hydrogen atom or a methoxy group and R2 represents a hydrogen atom or R1 and R2 taken together form a ring bond, and R3 represents a hydrogen atom, a nicotinoyl or substituted nicotinoyl group or a 1-oxo-2-cyclopenten-3-yl group; and further provides pharmaceutically acceptable salts of such ergoline derivatives. When R3 represents a substituted nicotinoyl group, the substituent is preferably an alkyl group having from to 4 carbon atoms, a nitro, cyano, hydroxy, amino or aminomethyl group, or a halogen atom such as a bromine atom. R4 is independently a C1-4 alkyl group, preferably methyl, such that (R4)3 C is a t-alkyl group.
1-(t-butyl)-10-methoxy-6-methyl-8β-hydroxymethylergoline, 1-(t-butyl) 10 methoxy-6-methyl-8β-(5-bromo-3-pyridine-carboxymethyl)-ergoline and 1-(t-butyl)-10-methoxy- 6-methyl-6β-(1-oxo-2-cyclopenten-3-yloxymethyl)ergoline are some of the preferred compounds of the invention.
The compounds of the invention may be administered in the form of a pharmaceutically acceptable acid addition salt. Such salt forms have the same order of activity as the free base forms.
The tertiary alkyl ergoline derivatives of the invention may be produced by reacting lysergol with an excess quantity of a tertiary alkyl alcohol, e.g., t-butanol, in the presence of a catalytic amount of trifluroacetic anhydride, in the presence or absence of an inert organic solvent, at a temperature between 15° and 30° C. for 70 to 90 hours, preferably at 20°-25° C. for 70-90 hours.
The 1-tertiary alkylated lysergol is then either hydrogenated in the presence of a noble metal catalyst, or alkoxylated upon UV irradiation in the presence of an alcohol and sulfuric acid, to form a 1-tertiaryalkylergoline derivative.
The compounds of the general formula I wherein R3 represents a hydrogen atom may be converted into other compounds of the general formula I using normal chemical reactions. For example the esterification of the C-17 hydroxy group is effected by treatment with the anhydride or chloride of an organic acid in the optional presence of a tertiary amine such as pyridine, triethylamine and the like, according to the method described in U.S. Pat. No. 3,228,943 (incorporated by reference herein). The etherification is effected by treatment of the corresponding tosyl esters with 1,3-dicarbonyl compounds in sodium salt form in hexamethylphosphotriamide as solvent as described in U.S. Pat. No. 4,382,940 (incorporated by reference herein). Preferably, this etherification is carried out by reaction with 1,3-cyclopentendione for 2-4 hours at a temperature between 70° C.-100° C.
It has been found that the presence of a t-butyl group in the position 1 of the ergoline skeleton is advantageous in comparison to the presence of a methyl group (U.S. Pat. No. 3,879,554) as shown by electroencephalographic effects (EEG) which show increased and longer-lasting modifications in terms of cortical activation. These modifications suggest the clinical usefulness of these derivatives for the following conditions: diffuse cerebral arteriosclerosis, transient cerebral ischemia and involution syndromes of presenile age, senescence and senility (Buonamici, M., Young, G.A. and Khazan (1982) Neuropharmacology 21 : 825-829, "Effects of Acute Δ9 -THC Administration on EEG and EEG Power Spectra in the Rat").
In this test the compounds were administered at doses of 5-10-20 mg/kg p.o. to groups of 8 rats.
The oral orientative acute toxicity (LD50) of the compounds of the formula I was higher than 800 mg/kg.
The compounds are therefore useful in the treatment of cerebral insufficiency and senile dementia, particularly the early stages thereof. For this use the dosage will, of course, vary depending on the compound employed, mode of administration and treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from 0.001 mg to about 50 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammal, the total daily dosage is in the range of from 1 to about 100, preferably 10 to 90 mg, and dosage forms suitable for oral administration comprise from about 0.2 mg to about 50 mg of the compounds admixed with a solid or liquid pharmaceutically acceptable carrier or diluent, such as starch, lactose, dextrin, magnesium stearate or water.
The present invention accordingly provides a pharmaceutical composition comprising at least one ergoline derivative I as herein defined or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in a conventional manner so as to be, for example, a solution or a tablet. The compounds of the present invention may be used in an analogous manner to standard compounds used for the indications mentioned above.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
EXAMPLE 1 1-(t-Butyl)-9,10-didehydro-6-methyl-8β-hydroxymethylergoline
To a mixture of 8 g of lysergol in 150 ml of t-butanol, 200 ml of trifluoroacetic anhydride were added dropwise with vigorous stirring. After the solution had been left at room temperature for 90 hours, it was evaporated. The residue was dissolved in water, made alkaline with ammonium hydroxide and the aqueous layer was extracted with ethyl acetate. After removal of the ethyl acetate, the residue was purified by silica gel column chromatography using 1:1 cyclohexane:ethyl acetate for elution to give 6 g of the title compound melting at 181° to 183° C.
EXAMPLE 2 1-(t-Butyl)-10-methoxy-6-methyl-8β-hydroxymethylergoline
A solution of 6 g of 1-(t-butyl)-9,10-didehydro-6- methyl-8β-hydroxymethyl-ergoline, prepared as described in Example 1, in 500 ml of methanol and 5 ml of sulphuric acid was irradiated at 20° C. in a Pyrex flask with a Hanau PL 321 lamp for about 6 hours, until the absorption at 315 nm completely disappeared. The solution was diluted with iced water, made basic with ammonium hydroxide, evaporated to 100 ml and extracted with ethyl acetate. After evaporation of the solvent the residue was chromatographed in silica gel and on elution with 97:3 dichloromethane:methanol, 5 g of the title compound was isolated, m.p. 172° to 174° C. from acetone.
EXAMPLE 3 1-(t-Butyl)-10-methoxy-6-methyl-8β-(5-bromo-3-pyridine- carboxymethyl)-ergoline
2.65 g of 5-bromonicotinoyl chloride were added at 25° C. to a solution of 3 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-hydroxymethyl-ergoline prepared as described in Example 2, in 35 ml of pyridine. After 4 hours the solution was evaporated in vacuo, the residue was taken up in water containing ammonium hydroxide and extracted with dichloromethane. Evaporation of the solvent left a residue that was purified by chromatography over silica gel using cyclohexane with increasing amounts of acetone (from 0 to 30 percent) as the eluant, to give 4 g of the title compound melting at 75° to 77° C.
EXAMPLE 4 1-(t-Butyl)-10-methoxy-6-methyl-8β-(1-oxo-2-cyclo- penten-3-yloxymethyl)-ergoline
(a) To a solution of 1.8 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-hydroxymethyl-ergoline, prepared as described in Example 2, in 20 ml of pyridine, 2.8 g of tosyl chloride in 15 ml of pyridine were slowly added. After the addition had been completed, the mixture was stirred for about six hours and was then poured into cold water and extracted with dichloromethane. The organic layer was evaporated off and the residue was chromatographed over 18 g of silica gel using dichloromethane with increasing amounts of methanol (from 0 to 4 percent) as the eluant. 2 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-tosyloxymethyl-ergoline were obtained, melting at about 150° to 152° C.
(b) A mixture of 2 g of the compound prepared in the first part of this Example and 0.7 g of 1,3-cyclopentandione sodium salt in 15 ml of hexamethylphosphotriamide was heated at 80° C. for 3 hours. The resulting solution was poured into 200 ml of water and the suspension was extracted with ethyl acetate. After evaporation of the organic solvent the residue was purified by crystallization from diethyl ether to give 1.5 g of the title compound, m.p. 145° to 147° C.
EXAMPLE 5 1-(t-Butyl-6-methyl-8β-hydroxymethyl-ergoline
A solution of 4 g of 1-(t-butyl)-9,10-didehydro-6- methyl-8β-hydroxymethyl-ergoline, prepared as described in Example 1, in 500 ml of methanol was hydrogenated in the presence of 4 g of 10% palladium on carbon catalyst. After removing the catalyst by filtration and the methanol by evaporation, the residue was crystallized from water:methanol to give 3 g of the title compound melting at 162° to 164° C.
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims (3)

What is claimed as new and desired to be secured by Letters Patent of the United States is:
1. An ergoline derivative having the formaula I ##STR5## wherein R1 and R2 taken together represent a ring bond; or
R1 is a hydrogen atom or a methoxy group and R2 is a hydrogen atom; and
R3 is a 1-oxo-2-cyclopenten-3-yl group; or a pharmaceutically acceptable salt thereof.
2. An ergoline derivative according to claim 1, wherein said derivative is 1-(t-butyl)-10-methoxy-6-methyl-8β-(1-oxo-2-cyclo-penten-3-yloxymethyl)-ergoline.
3. A pharmaceutical composition comprising a pharmaceutically effective amount of an ergoline derivative according to claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
US07/065,597 1986-06-25 1987-06-23 1-t-butyl ergolines useful in the treatment of cerebral insufficiency and senile dementia Expired - Fee Related US4843073A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014195849A3 (en) * 2013-06-03 2015-07-30 Cellixbio Private Limited Compositions and methods for the treatment of cerebrovascular diseases

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61245164A (en) * 1985-04-23 1986-10-31 Seiko Instr & Electronics Ltd Pattern correcting device
HU193782B (en) * 1985-06-21 1987-11-30 Richter Gedeon Vegyeszet Process for producing 2-halogeno-nicergoline derivatives and acid additional salts thereof
US6060483A (en) * 1996-06-27 2000-05-09 Pharmacia & Upjohn S.P.A. Antineurodegenerative ergoline derivatives

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE203721C (en) * 1908-05-05
US3228945A (en) * 1966-01-11 Methyl and i,g-dimethyl-b-(a-hydroxy- alkyl)-ergoline i derivatives
US3228941A (en) * 1966-01-11 Methyl and i,g-dimethyl-ergoline i derivatives
US3228942A (en) * 1966-01-11 Methyl and i,g-dimeti-iyl ergoline i compounds
US3232942A (en) * 1964-06-02 1966-02-01 Sandoz Ltd 1-substituted (+)-lysergol
US3879554A (en) * 1970-03-20 1975-04-22 Farmaceutici Italia Use of 1,6-dimethyl-8-{62 -(5-bromonicotinoyloxymethyl)-10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders
US4199579A (en) * 1975-03-14 1980-04-22 Siphar S. A. Carbamates of 2-haloergolines and 2-haloergolenes and process for the preparation thereof
GB2056437A (en) * 1979-08-07 1981-03-18 Erba Farmitalia Secoergoline derivatives
US4348391A (en) * 1975-12-23 1982-09-07 Sandoz Ltd. Sulfonamido and sulfamoylamino-ergoline-I derivatives
US4382940A (en) * 1979-12-06 1983-05-10 Farmitalia Carlo Erba S.P.A. Ercoline derivatives and therapeutic compositions having CNS affecting activity

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE30218E (en) * 1974-12-06 1980-02-19 Eli Lilly And Company 8,8-Disubstituted-6-methylergolines and related compounds
US3959288A (en) * 1974-12-13 1976-05-25 Eli Lilly And Company 8-Oxymethylergolines and process therefor
IT1192260B (en) * 1977-07-05 1988-03-31 Simes ERGOLINE-2-THIOETHERS AND THEIR SULPHOXIDES DERIVATIVES
DE3403067A1 (en) * 1984-01-30 1985-08-14 Eckart Prof. Dr. 6500 Mainz Eich Ergoline derivatives, process for their preparation, medicaments containing them and their use
IT1213206B (en) * 1984-08-07 1989-12-14 Inverni Della Beffa Spa PROCEDURE FOR THE PREPARATION OF LYSERGOL DERIVATIVES.
GB8612366D0 (en) * 1986-05-21 1986-06-25 Erba Farmitalia Ergoline esters
AU7914587A (en) * 1987-08-24 1989-03-31 Molecular Control Corporation Liquid crystal micelles, display, having concentric spheres

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3228945A (en) * 1966-01-11 Methyl and i,g-dimethyl-b-(a-hydroxy- alkyl)-ergoline i derivatives
US3228941A (en) * 1966-01-11 Methyl and i,g-dimethyl-ergoline i derivatives
US3228942A (en) * 1966-01-11 Methyl and i,g-dimeti-iyl ergoline i compounds
DE203721C (en) * 1908-05-05
US3232942A (en) * 1964-06-02 1966-02-01 Sandoz Ltd 1-substituted (+)-lysergol
US3879554A (en) * 1970-03-20 1975-04-22 Farmaceutici Italia Use of 1,6-dimethyl-8-{62 -(5-bromonicotinoyloxymethyl)-10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders
US4199579A (en) * 1975-03-14 1980-04-22 Siphar S. A. Carbamates of 2-haloergolines and 2-haloergolenes and process for the preparation thereof
US4348391A (en) * 1975-12-23 1982-09-07 Sandoz Ltd. Sulfonamido and sulfamoylamino-ergoline-I derivatives
GB2056437A (en) * 1979-08-07 1981-03-18 Erba Farmitalia Secoergoline derivatives
US4382940A (en) * 1979-12-06 1983-05-10 Farmitalia Carlo Erba S.P.A. Ercoline derivatives and therapeutic compositions having CNS affecting activity

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
Arcamone et al, CA 77 28736h (1972) Metabolism of Ergoline Derivatives . *
Arcamone et al, CA 77-28736h (1972) "Metabolism of Ergoline Derivatives".
Arcari et al, CA 77 135024w (1972) Ergoline Derivatives . *
Arcari et al, CA 77-135024w (1972) "Ergoline Derivatives".
Bernardi et al, CA 61 3160g (1964) New Derivatives of Lumilysergol . *
Bernardi et al, CA 61-3160g (1964) "New Derivatives of Lumilysergol".
Bernardi et al, CA 84 44500b Ergoline Derivatives, XIII . *
Bernardi et al, CA 84-44500b "Ergoline Derivatives, XIII".
Bernardi et al, CA 88 182447y (1978) Ergoline Derivatives with Oral Prolonged Adrenolytic Activity . *
Bernardi et al, CA 88-182447y (1978) "Ergoline Derivatives with Oral Prolonged α-Adrenolytic Activity".
Cerny et al, CA 105 209252q (1986) D 1,6 Dimethyl 8 (5 bromonicotinoyl)oxy methyl 10 ethoxyergoline . *
Cerny et al, CA 105-209252q (1986) "D-1,6-Dimethyl-8β-[[(5-bromonicotinoyl)oxy]-methyl]-10α-ethoxyergoline".
Fregman, CA 81 114605d (1974) Inhibition of Platelet Aggregation by Anti 5 Hydroxytryptaminic and Alpha Adrenergic Blocking Agent . *
Fregman, CA 81-114605d (1974) "Inhibition of Platelet Aggregation by Anti-5-Hydroxytryptaminic and Alpha-Adrenergic Blocking Agent".
Gasco, CA 83 114707e (1975) Charge Transfer Complexes of Indolealkylamine and Ergoline Derivatives . *
Gasco, CA 83-114707e (1975) "Charge-Transfer Complexes of Indolealkylamine and Ergoline Derivatives".
Hofmann et al, CA 64 12748e (1966) 1 substituted ( ) lysergols and 9,10 dihydro ( ) lysergols . *
Hofmann et al, CA 64-12748e (1966) "1-substituted-(+)-lysergols and -9,10-dihydro-(+)-lysergols".
Sandoz Ltd. CA 57 15173b, 1962 Lysergol Derivatives . *
Sandoz Ltd. CA 57-15173b, 1962 "Lysergol Derivatives".
Troxler et al, Helv. Chim. Acta. 40, pp. 2160 2170 (1957). *
Troxler et al, Helv. Chim. Acta. 40, pp. 2160-2170 (1957).
Yamada et al, CA 105 18148a (1986) General Pharmacology of Nicergoline, a Cerebral Circulation and Metabolism Ameliorator (2) . *
Yamada et al, CA 105-18148a (1986) "General Pharmacology of Nicergoline, a Cerebral Circulation and Metabolism Ameliorator (2)".

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014195849A3 (en) * 2013-06-03 2015-07-30 Cellixbio Private Limited Compositions and methods for the treatment of cerebrovascular diseases

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DE3779190D1 (en) 1992-06-25
IE61319B1 (en) 1994-11-02
SU1547708A3 (en) 1990-02-28
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FI85702C (en) 1992-05-25
HU196201B (en) 1988-10-28
CA1339533C (en) 1997-11-11
IE871652L (en) 1987-12-25
HUT44543A (en) 1988-03-28
DK170099B1 (en) 1995-05-22
EP0251652B1 (en) 1992-05-20
ES2042567T3 (en) 1993-12-16
GB8615471D0 (en) 1986-07-30
PT85152B (en) 1990-03-30
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ATE76407T1 (en) 1992-06-15
US5079364A (en) 1992-01-07
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GR3005115T3 (en) 1993-05-24

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